Home LiteratureArticle Details
PMID: 36351856 Published · ppublish English Journal Article Review Research Support, Non-U.S. Gov't

The impact of paternal age on new mutations and disease in the next generation.

Fertility and sterility ·Vol. 118 ·No. 6 ·2022-00-00 ·Pages 1001-1012

Wood KA, Goriely A

Abstract

Advanced paternal age is associated with an increased risk of fathering children with genetic disorders and other adverse reproductive consequences. However, the mechanisms underlying this phenomenon remain largely unexplored. In this review, we focus on the impact of paternal age on de novo mutations that are an important contributor to genetic disease and can be studied both indirectly through large-scale sequencing studies and directly in the tissue in which they predominantly arise-the aging testis. We discuss the recent data that have helped establish the origins and frequency of de novo mutations, and highlight experimental evidence about the close link between new mutations, parental age, and genetic disease. We then focus on a small group of rare genetic conditions, the so-called "paternal age effect" disorders that show a strong association between paternal age and disease prevalence, and discuss the underlying mechanism ("selfish selection") and implications of this process in more detail. More broadly, understanding the causes and consequences of paternal age on genetic risk has important implications both for individual couples and for public health advice given that the average age of fatherhood is steadily increasing in many developed nations.

Keywords
Paternal age effect complex disorders rare disorders selfish selection spermatogonial stem cells
MeSH Terms
Humans Male Aging Mutation Paternal Age Testis
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Wood Katherine A
Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom.
Goriely Anne
Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, Oxford, United Kingdom. Electronic address: [email protected].
References (104)
104 references, click to expand
  1. British Andrology Society guidelines for the screening of semen donors for donor insemination (1999).
    Hum Reprod. 1999 Jul;14(7):1823-6 PMID: 10402397
  2. Advanced Paternal Age and Future Generations.
    Front Endocrinol (Lausanne). 2022 Jun 09;13:897101 PMID: 35757433
  3. New observations on maternal age effect on germline de novo mutations.
    Nat Commun. 2016 Jan 19;7:10486 PMID: 26781218
  4. Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective.
    Schizophr Res. 2011 Dec;133(1-3):120-4 PMID: 22000939
  5. Human TKTL1 implies greater neurogenesis in frontal neocortex of modern humans than Neanderthals.
    Science. 2022 Sep 9;377(6611):eabl6422 PMID: 36074851
  6. The molecular anatomy of spontaneous germline mutations in human testes.
    PLoS Biol. 2007 Sep;5(9):e224 PMID: 17760502
  7. Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia.
    Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6051-6 PMID: 15840724
  8. Statement on guidance for genetic counseling in advanced paternal age.
    Genet Med. 2008 Jun;10(6):457-60 PMID: 18496227
  9. Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.
    Science. 2021 May 14;372(6543):725-729 PMID: 33888597
  10. Advanced paternal age and stillbirth rate: a nationwide register-based cohort study of 944,031 pregnancies in Denmark.
    Eur J Epidemiol. 2017 Mar;32(3):227-234 PMID: 28271174
  11. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
    Nature. 2017 Sep 28;549(7673):519-522 PMID: 28959963
  12. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.
    Genome Res. 2018 Dec;28(12):1779-1790 PMID: 30355600
  13. Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study.
    Br J Cancer. 2002 Feb 1;86(3):356-61 PMID: 11875699
  14. Paternal age at birth of first child and risk of schizophrenia.
    Am J Psychiatry. 2011 Jan;168(1):82-8 PMID: 20952457
  15. Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004.
    Ann Epidemiol. 2010 Mar;20(3):241-9 PMID: 20056435
  16. Guidelines for sperm donation.
    Fertil Steril. 2004 Sep;82 Suppl 1:S9-12 PMID: 15363683
  17. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.
    Am J Hum Genet. 2014 May 1;94(5):677-94 PMID: 24768552
  18. Chromatin and Single-Cell RNA-Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development.
    Cell Stem Cell. 2017 Oct 5;21(4):533-546.e6 PMID: 28985528
  19. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect.
    Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14952-7 PMID: 12397172
  20. Multiple transmissions of de novo mutations in families.
    Nat Genet. 2018 Dec;50(12):1674-1680 PMID: 30397338
  21. Gonadal mosaicism and non-invasive prenatal diagnosis for 'reassurance' in sporadic paternal age effect (PAE) disorders.
    Prenat Diagn. 2017 Sep;37(9):946-948 PMID: 28686291
  22. Large, three-generation human families reveal post-zygotic mosaicism and variability in germline mutation accumulation.
    Elife. 2019 Sep 24;8: PMID: 31549960
  23. The effects of advanced paternal age on fertility.
    Asian J Androl. 2013 Nov;15(6):723-8 PMID: 23912310
  24. No evidence of increased mutations in the germline of a group of British nuclear test veterans.
    Sci Rep. 2022 Jul 5;12(1):10830 PMID: 35790751
  25. Genetic and chemotherapeutic influences on germline hypermutation.
    Nature. 2022 May;605(7910):503-508 PMID: 35545669
  26. Parental age and risk of childhood cancers: a population-based cohort study from Sweden.
    Int J Epidemiol. 2006 Dec;35(6):1495-503 PMID: 17008361
  27. De novo mutations in children born after medical assisted reproduction.
    Hum Reprod. 2022 May 30;37(6):1360-1369 PMID: 35413117
  28. The importance of father's age to schizophrenia risk.
    Mol Psychiatry. 2014 May;19(5):530-1 PMID: 23711980
  29. The Neonatal and Adult Human Testis Defined at the Single-Cell Level.
    Cell Rep. 2019 Feb 5;26(6):1501-1517.e4 PMID: 30726734
  30. Genetic effects of radiation in atomic-bomb survivors and their children: past, present and future.
    J Radiat Res. 2006;47 Suppl B:B67-73 PMID: 17019054
  31. Paternal age and adverse birth outcomes: teenager or 40+, who is at risk?
    Hum Reprod. 2008 Jun;23(6):1290-6 PMID: 18256111
  32. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis.
    Cell Rep. 2013 Jun 27;3(6):2179-90 PMID: 23791531
  33. Autism risk across generations: a population-based study of advancing grandpaternal and paternal age.
    JAMA Psychiatry. 2013 May;70(5):516-21 PMID: 23553111
  34. Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection.
    Am J Hum Genet. 2013 Jun 6;92(6):917-26 PMID: 23726368
  35. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies.
    Mol Psychiatry. 2011 Dec;16(12):1203-12 PMID: 21116277
  36. Differences between germline and somatic mutation rates in humans and mice.
    Nat Commun. 2017 May 09;8:15183 PMID: 28485371
  37. Higher Germline Mutagenesis of Genes with Stronger Testis Expressions Refutes the Transcriptional Scanning Hypothesis.
    Mol Biol Evol. 2020 Nov 1;37(11):3225-3231 PMID: 32638015
  38. The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect.
    PLoS Genet. 2009 Jul;5(7):e1000558 PMID: 19593369
  39. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.
    Science. 2003 Aug 1;301(5633):643-6 PMID: 12893942
  40. Assisted reproductive technologies do not alter mutation frequency or spectrum.
    Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5085-90 PMID: 17360354
  41. Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes.
    Proc Natl Acad Sci U S A. 2019 Sep 3;116(36):17916-17924 PMID: 31427530
  42. Age and sex effects on human mutation rates: an old problem with new complexities.
    J Radiat Res. 2006;47 Suppl B:B75-82 PMID: 17019055
  43. A comprehensive assessment of parental age and psychiatric disorders.
    JAMA Psychiatry. 2014 Mar;71(3):301-9 PMID: 24452535
  44. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors.
    Nat Genet. 2009 Nov;41(11):1247-52 PMID: 19855393
  45. Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation.
    Am J Hum Genet. 2015 Jul 2;97(1):67-74 PMID: 26054435
  46. Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies.
    Fertil Steril. 2008 Jun;89(6):1651-6 PMID: 17706214
  47. A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.
    Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10143-8 PMID: 18632557
  48. Mutational signatures: emerging concepts, caveats and clinical applications.
    Nat Rev Cancer. 2021 Oct;21(10):619-637 PMID: 34316057
  49. Prevalence and architecture of de novo mutations in developmental disorders.
    Nature. 2017 Feb 23;542(7642):433-438 PMID: 28135719
  50. Association between paternal age and risk of schizophrenia: a nationwide population-based study.
    J Assist Reprod Genet. 2021 Jan;38(1):85-93 PMID: 32862335
  51. Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation.
    Nat Commun. 2023 Feb 15;14(1):853 PMID: 36792598
  52. Timing, rates and spectra of human germline mutation.
    Nat Genet. 2016 Feb;48(2):126-133 PMID: 26656846
  53. Differences in the number of de novo mutations between individuals are due to small family-specific effects and stochasticity.
    Genome Res. 2021 Sep;31(9):1513-1518 PMID: 34301630
  54. The impact of chemo- and radiotherapy treatments on selfish de novo FGFR2 mutations in sperm of cancer survivors.
    Hum Reprod. 2019 Aug 1;34(8):1404-1415 PMID: 31348830
  55. Association of paternal age at birth and the risk of breast cancer in offspring: a case control study.
    BMC Cancer. 2005 Oct 31;5:143 PMID: 16259637
  56. Epidemiological studies of atomic bomb radiation at the Radiation Effects Research Foundation.
    Int J Radiat Biol. 2019 Jul;95(7):879-891 PMID: 30676179
  57. Parent-of-origin-specific signatures of de novo mutations.
    Nat Genet. 2016 Aug;48(8):935-9 PMID: 27322544
  58. Cellular evidence for selfish spermatogonial selection in aged human testes.
    Andrology. 2014 May;2(3):304-14 PMID: 24357637
  59. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease.
    Am J Hum Genet. 2012 Feb 10;90(2):175-200 PMID: 22325359
  60. The adult human testis transcriptional cell atlas.
    Cell Res. 2018 Dec;28(12):1141-1157 PMID: 30315278
  61. Rate of de novo mutations and the importance of father's age to disease risk.
    Nature. 2012 Aug 23;488(7412):471-5 PMID: 22914163
  62. Paternal age and preterm birth in Italy, 1990 to 1998.
    Epidemiology. 2006 Mar;17(2):218-21 PMID: 16477263
  63. Evidence for 28 genetic disorders discovered by combining healthcare and research data.
    Nature. 2020 Oct;586(7831):757-762 PMID: 33057194
  64. Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing.
    PLoS One. 2016 Jun 24;11(6):e0158340 PMID: 27341568
  65. Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B.
    PLoS Genet. 2012;8(2):e1002420 PMID: 22359510
  66. Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.
    Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20152-7 PMID: 24259709
  67. Determinants of mutation rate variation in the human germline.
    Annu Rev Genomics Hum Genet. 2014;15:47-70 PMID: 25000986
  68. The origins, patterns and implications of human spontaneous mutation.
    Nat Rev Genet. 2000 Oct;1(1):40-7 PMID: 11262873
  69. A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex.
    Nat Genet. 2022 Sep;54(9):1284-1292 PMID: 35654974
  70. Understanding the association between advanced paternal age and schizophrenia and bipolar disorder.
    Psychol Med. 2020 Feb;50(3):431-437 PMID: 30827282
  71. Human genomics. The human transcriptome across tissues and individuals.
    Science. 2015 May 8;348(6235):660-5 PMID: 25954002
  72. Advanced paternal age and risk of schizophrenia in offspring - Review of epidemiological findings and potential mechanisms.
    Schizophr Res. 2021 Jul;233:72-79 PMID: 34242951
  73. Genome-wide patterns and properties of de novo mutations in humans.
    Nat Genet. 2015 Jul;47(7):822-826 PMID: 25985141
  74. Paternal-age-related de novo mutations and risk for five disorders.
    Nat Commun. 2019 Jul 10;10(1):3043 PMID: 31292440
  75. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder.
    Nat Neurosci. 2016 Nov;19(11):1454-1462 PMID: 27479844
  76. "Selfish spermatogonial selection": a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders.
    Am J Psychiatry. 2013 Jun;170(6):599-608 PMID: 23639989
  77. A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing.
    Genome Med. 2019 Jul 26;11(1):48 PMID: 31349857
  78. New evidence for positive selection helps explain the paternal age effect observed in achondroplasia.
    Hum Mol Genet. 2013 Oct 15;22(20):4117-26 PMID: 23740942
  79. Signatures of mutational processes in human cancer.
    Nature. 2013 Aug 22;500(7463):415-21 PMID: 23945592
  80. The Effects of Parent Ages on Birth Defects.
    Acta Sci Paediatr. 2020 Oct;3(10):58-69 PMID: 35799686
  81. The mutational landscape of human somatic and germline cells.
    Nature. 2021 Sep;597(7876):381-386 PMID: 34433962
  82. Spontaneous mutation and parental age in humans.
    Am J Hum Genet. 1987 Aug;41(2):218-48 PMID: 3618593
  83. Rare variants and the oligogenic architecture of autism.
    Trends Genet. 2022 Sep;38(9):895-903 PMID: 35410794
  84. Somatic mutation landscapes at single-molecule resolution.
    Nature. 2021 May;593(7859):405-410 PMID: 33911282
  85. Widespread Transcriptional Scanning in the Testis Modulates Gene Evolution Rates.
    Cell. 2020 Jan 23;180(2):248-262.e21 PMID: 31978344
  86. De Novo Mutations Reflect Development and Aging of the Human Germline.
    Trends Genet. 2019 Nov;35(11):828-839 PMID: 31610893
  87. Advanced paternal age: how old is too old?
    J Epidemiol Community Health. 2006 Oct;60(10):851-3 PMID: 16973530
  88. Genetic Effect of Chemotherapy Exposure in Children of Testicular Cancer Survivors.
    Clin Cancer Res. 2016 May 1;22(9):2183-9 PMID: 26631610
  89. Advancing paternal age and the risk of schizophrenia.
    Arch Gen Psychiatry. 2001 Apr;58(4):361-7 PMID: 11296097
  90. Developmental and temporal characteristics of clonal sperm mosaicism.
    Cell. 2021 Sep 2;184(18):4772-4783.e15 PMID: 34388390
  91. Overlooked roles of DNA damage and maternal age in generating human germline mutations.
    Proc Natl Acad Sci U S A. 2019 May 7;116(19):9491-9500 PMID: 31019089
  92. Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study.
    BMJ. 2018 Oct 31;363:k4372 PMID: 30381468
  93. Beyond Genes: Germline Disruption in the Etiology of Autism Spectrum Disorders.
    J Autism Dev Disord. 2022 Oct;52(10):4608-4624 PMID: 34596807
  94. Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline.
    PLoS One. 2017 May 22;12(5):e0178169 PMID: 28542371
  95. Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations.
    Nat Genet. 2016 Jul;48(7):718-24 PMID: 27213288
  96. The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015.
    Hum Reprod. 2017 Oct 1;32(10):2110-2116 PMID: 28938735
  97. Rates of contributory de novo mutation in high and low-risk autism families.
    Commun Biol. 2021 Sep 1;4(1):1026 PMID: 34471188
  98. Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes.
    Proc Natl Acad Sci U S A. 2016 Mar 1;113(9):2454-9 PMID: 26858415
  99. New insights into the generation and role of de novo mutations in health and disease.
    Genome Biol. 2016 Nov 28;17(1):241 PMID: 27894357
  100. Single-cell RNA-seq unravels alterations of the human spermatogonial stem cell compartment in patients with impaired spermatogenesis.
    Cell Rep Med. 2021 Sep 09;2(9):100395 PMID: 34622232
  101. Single-Cell RNA Sequencing of Human, Macaque, and Mouse Testes Uncovers Conserved and Divergent Features of Mammalian Spermatogenesis.
    Dev Cell. 2020 Aug 24;54(4):529-547.e12 PMID: 32504559
  102. Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms.
    Transl Psychiatry. 2017 Jan 31;7(1):e1019 PMID: 28140401
  103. The Sins of Our Forefathers: Paternal Impacts on De Novo Mutation Rate and Development.
    Annu Rev Genet. 2020 Nov 23;54:1-24 PMID: 32663048
  104. Maternal age in the epidemiology of common autosomal trisomies.
    Prenat Diagn. 2021 Apr;41(5):573-583 PMID: 33078428
Article Info
Journal
Fertility and sterility
Abbr.
Fertil Steril
ISSN
1556-5653
DOI
10.1016/j.fertnstert.2022.10.017
Email
[email protected]
Published
2022-00-00
Epub
2022-00-06
Pages
1001-1012
Language
English
Region
United States
NLM ID
0372772
PMCID
PMC10909733
Subset
IM
Grants
Wellcome Trust · United Kingdom
Wellcome Trust · 219476/Z/19/Z · United Kingdom
Department of Health · United Kingdom
External Links
PubMed source DOI: 10.1016/j.fertnstert.2022.10.017 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2